Amino-substituted butanols as cough-depressants



United States Patent 3,121,087 AMINO-SUBSTITUTED BUTANQLS AS COUGH-BEERESSANIS Alex Berg, Biherach an der Rise, Germany, assignor to Dr. Karl Thomae G.ni.h.H., Biherach an der Riss, Germany, a corporation of Germany No Drawing. Filed June 28, 1961, Ser. No. 120,193 10 Claims. (Cl. 260-294.7)

This is a continuation-in-part of copending application Serial No. 15,835 filed March 18, 1960, now abandoned.

This invention relates to basic substituted carbinols and to various methods of preparing the same.

More particularly, the present invention relates to basicsubstituted carbinols of the formula wherein:

their racemates, optically active antipodes and non-toxic, pharmacologicaly acceptable acid addition salts.

It should be noted that the compounds of the present invention have the essential structural characteristic that the phenyl group and the amino group are separated by a chain of 4 carbon atoms the two middle carbon atoms of which are asymmetric carbon atoms where optical isomerism is possible.

The compounds according to the present invention may e prepared by several conventient methods.

For example, they may be prepared by reacting ketones of the general formula l R2(LJ(IJHCH2N Ra R (II) wherein R R R and R have the meanings previously defined, with Grignard reagents of the general formula CH2MgX (III) wherein R has the meanings defined above and X is halogen.

Another method of preparing the compounds of the present invention comprises reacting ketones of the formula "ice wherein R R R and R have the meanings previously defined, with a Grignard reagent of the formula R MgX (V) wherein R has the meaning defined above and X is halogen.

Similarly, they may he prepared by reacting basicsubstituted propionic acid esters of the general formula Rs s wherein R R and R have the meanings previously defined and R is lower alkyl, with both of the Grignard reagents of the Formulas III and V. In this method of preparation the basic propionic acid ester VI may be reacted with the two Grignard compounds in any desired sequence or even with both at the same time. This latter variation, that is, reaction of the basic propionic acid ester with both Grignard reagents simultaneously, represents a particularly advantageous method of preparing the carbinols of the present invention because it makes it possible to obtain the desired carbinols by a single step process from the readily accessible basic propionic acid esters.

The processes described above are carried out under conditions which are customarily used in Grignard reac tions. Thus, the reactions are carried out in the presence of an anhydrous inert solvent, such as ether, benzene, tetrahydrofuran or mixtures thereof. As the first step, the deired Grignard reagent III or V is prepared from the corresponding halide by well known procedures; in the case of the reaction of the basic propionic acid ester with both Grignard reagents simultaneously, the mixed Grignard reagent is prepared from a mixture of the corresponding halides. Thereafter, the ketone of the Formula II or IV or the propionic acid ester VI is added dropwise to the Grignard reagent solution, preferably while cooling the reaction mixture of an ice bath. After all of the ketone or basic propionic acid ester has been added the reaction is brought to completion, if necessary, by heating the reaction mixture on a water bath. Thus, the reaction is advwtageously carried out at temperatures between 0 and C. The quantitative ratio of reactants in the reaction between ketones II or IV and Grignard compounds III or V, respectively, is 1 to 3 mols Grignard compound per mol of ketone; in the reaction between the propionic acid ester VI and the Grignard compounds the quantitative ratio is 1 to 3 mols of each of the Grignard compounds per mol of propionic acid ester.

The substantially anhydrous reaction mixture obtained in each of the above methods is worked up in the usual manner, that is, by pouring it over ice, decomposing the resulting aqueous mixture into an aqueous and an organic phase with a strong acid, isolating the basic carbinol from the aqueous phase and purifying it by distillation. If de- 'red, the free basic carbinol may then be transformed into any desired pharmacologically non-toxic acid addition salt with a physiologically compatible acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, succinic acid and the like. The free bases and their acid addition salts may be divided into their two possible racemic forms by customary methods, such as by fractional crystallization. The racemic compounds may then, in turn, be separated into their optical antipodes by customary methods, such as by fractional crystallization of their salts with dibenZOyLa-tartaric acid or dbromo-camphor-sulfonic acid.

The basic ketones of the Formulas II and IV may be prepared from the corresponding ketones, for example, with formaldehyde and a suitable secondary amine. The method of preparation of ketones of the Formulas II and IV is described by Mannich in Archiv der Pharmazie, vol. 264, page 741 (1926) Journal of Organic Chemistry, vol. 18, page 736 (1953); and Journal of the Chemical Society, 1952, page 1,321.

The hydrochloride addition salt of the above reaction product was prepared in customary fashion, that is by reaction with hydrochloric acid, followed by fractional crystallization from a mixture or" alcohol and ether. The two possible racernic forms were obtained thereby. The

The basic propionic acid esters of the Formula Vl may most conveniently be prepared by the method described in difiicultly soluble racernate had a meltaing point of 169 to Houben-Weyl, vol. 11/1, page 279, i.e. by condensation of 170 C. and the more readily soluble racemate had a amines of the formula boiling point of 145 to 148 C. i

In addition to the hydrochloride, the followin acid /R4 a g H addition salts of the free base were prepared by reacting it with the corresponding acid:

(VII) s i t 1' t 189 0 u la e, me ting porn Q with acrylic acid esters of the formula Nltrata, mehmg point 0 Phosphate, melting point 148 C. (VIII) Acid tartrate, melting point 177 to 179 C.

. g wherein R R R and R have the meanings previously Acll meltmg 901m 104 defined.

The following examples will further illustrate the pres- E MPLE H ent invention and enable others skilled in the art to under- Preparation 07' 1-Phanyl-2,3-Dimeihyl-4-Dzmethylammostand it more completely. It is understood, however, that BIIMII Z-(Z) q f i the ingeimon 1s not limited to tne particular exampes A solution of 29 gm B dunemylammo a methy1p1.o g1 Jan 6 EXAVPLE I picnic acid methylester in 50 cc. ether was added dropwise over a period of twenty minutes, accompanied by Preparation of 1-p-Chlorophenyl-Z,S-DimezhyZ-4- 29 stirring and cooling with ice, to aGrignard solution which Dimethylamino-Buranol-(2) had been prepared from 35.5 gm. methyliodide 7 A solution of mol (33 gm of 3-methyl-4-dimethylmol) 5 .benzillbmmlde (23/100 mol) and aminobutanomjc) [smduced according to Manpich magnesium turmngs m 209 cc. ether. After heating the Arch Phamn Vol also 589 (1927)] in 50 CC 5 reactlon mixture under reflux for one hour, 1t was de p f. f 30 composed into an ether phase and an aqueous phase with lute ether was added dropwise, while stirring and cooling a with ice to a Grimmrd Sohltim 4/0 mo} ndlolomenzyh a mixture of ice and concentrated hydrochloric acid. The 1 ether ohase was separated and discarded. The aqueous ma nesium-chloride which was produced from 64.5 gm.

1 n phase was ad usted to an alkaline pH value with amp-chiorooenzyl-chloride and 9. gm. ma nesrum in 2-00 cc. absolute ethnr The reacfkm rcduct ,jlas heated for an monia and was tnen thoroughly extracted with etner. The L ether extract solutions were combined, dried and the ether additional one-half hour under reflux LO bring the reaction m h A was tnen evaporated. For purmcation, the oily residue to completion, and thereauer the reaction mixture was deq d f 12 H t 142 t 0 C composed into an ether phase and an aqueous phase with s 1 g: ig g g ggg the 'i about 50 cc. concentrated hydrochloric acid and about 200 gg d i g gm. ice. The ether phase was discarded and the aqueous 40 phase was adjusted to an alkaline pH with ammonia and then thoroughly extracted with ether. After concentrat CH2 C- -CH CH2 N ing the united, dried ether extract solutions, the oily resi- (IDHK 1 due was fractionally distilled. The reaction product hav- 3 mg the sifucmr a1 formula in the form of a faintly yellow oil.

011 The following table shows eighteen additional basic- 01 substituted carbinols of the general Formula I which were prepared by the methods illustrated in Examples I CH3 CH3 C113 and H. The table lists the meanings of substituents R was obtained in the form of a colorless oil having a boiling through R of Formula I, the boiling point of the free base point of 179 to 181 C. The yield was 48.5 gm. corand/or the melting point of the hydrochloride addition responding to of theory. salt in each case.

TABLE Exa mple R1 R2 R3 R R Properties CH CH3 CH CH3 B.P. lac-152 C. at 12 mm. Hg. CH3 OHzO H5 CH3 CH3 B.P. 166-169 C. at 0.1 mm. Hg. 02H. CH3 CH3 CH3 B.P.161-163 C. at 12 mm. Hg. CH3 C6H5 CH3 CH3 figgi ogjhloride addition salt; M.P. VII -C1 C2115 CH3 CH3 OH; 13.1 1815-188" 0. at 12 mm. Hg. gydrzofibgride addition salt; M.P.

8- VIII p-CHa CH CH3 CH3 CH B.P.157-169 C. at 12 mm. Hg. IX H OH; GH CH CH CH3 B.P.l63167 C. at 12 mm.Hg.

l. X 0 01 CH CH3 2 CH3 cm 13.1. 171-173 C. at 12 mm. Hg. fgghmhloride addition salt: M.P. XI H CH3 02m CH3 CH3 B1. 162 164 0:11:12 mm. Hg. XII p-Cl CH C2115 CH3 CH3 B.P.187-188 Cat 12mm. Hg. XIII p-Cl CH CH3 C H C 11 HP. 205-203 C. at 15 mm. Hg.

XIV H CH3 CH3 CH CH B.P. 192-194 C. at 20 mm. Hg. Hydrochloride addition salt; IMP. CH CH2 206208 C.

TABLE-Continued Example R1 R2 R3 R4 R Properties N XV p-Cl CH CH3 CH CH B.P. 168-170 C. at 0.3 mm. Hg. Hydrochloride addition salt; MJ? CH2 CH2 215-217 C.

N XVI p-Cl CH3 CH (llH- CH B.P. 210215 C. at mm. Hg.

CH2CH2 XVII m-CH; CH CH OH; I CH3 B.P. 165-168" C. at 12 mm. Hg.

N XVIII H CH CH (IZII CH B.P. ZOO-203 C. at 20 mm. Hg.

CH3 CH2 XIX p-Br CH; CH CH3 CH3 B P 156160 C. at 0 mm Hg XX rn-Cl CH CH CH3 CH3 B P 182183 C. at 12 mm Hg The compounds of the present invention, that is, those embraced by Formula I above and their racernates, op tically active antipodes and non-toxic, pharmacologically acceptable acid addition salts, are very efiective bechics, i.e. cough-depressants, with an activity about as great as that of codeine, Whereas surprisingly they do not exhibit any noticeable analgesic activity, nor do they display the Well known undesirable side effects encountered with codeine. It is noteworthy that even t e racemates exhibit this surprising activity.

The mean individual elfective dose of l-p-chlorophenyl- 2,3-dimethyl-4-dimethylamino-butanol-(2), which is the compound illustrated in Example I, is from to 60 mgrn., and the mean daily effective dose is from 90 to 120 mgrn.

The compounds in accordance with the present invention may be administered in the form of dosage unit compositions, such as drops, syrups, tablets, coated pills, suppositories, ampoules or the like.

The following examples illustrate various dosage unit compositions adapted for internal administration of the compounds according to the present invention.

EXAMPLE XXI Drops:

p-Hydroxy-methyl benzoate grn 0.035 p-Hydroxy-propyl benzoate gm 0.015 Anise oil "gm" 0.05 Menthol grn 0.06 Ethanol (pure) gm 10.00

1-p-chlorophenyl-2,3-dimethly-4-dimethylaminobutanol-(Z) gm 6.00 Saccharin-sodium gm 1.00 Glycerin gm 15.00 Distilled water, q.s. ad cc 100.00

1 cc. contains 60 mgm. 1-p-chlor0phenyl-2,3-dimethyl- 4-dimethylarnino-butan0l- 2) The p-hydroxy benzoic esters, the anise oil and the menthol are dissolved in ethanol (solution A). The saccharin-sodiurn and the 1-p-chlorophenyl-2,3-dimethyl- 4-dimethylamino-butanol-(2) are dissolved in Water, and the glycerin is added thereto {solution B). Solutions A and B are then admixed With each other, and are then filtered until clear.

EXAPLE XXII Pectoral syrup:

1-p-chlorophenyl-2,3-dimethyl-4-dimethylamino-butanol-(Z) grn 0.50 Sugar gm 70.00 Tartaric acid (pure) grn 0.30 See. sodium phosphate.12H O gm 2.40 Saccharin-sodium gm 0.20 p-HydroXy-methyl benzoate gm 0.07 p-HydroXy-propyl benzoate gm 0.03 Eucalyptus-menthol flavoring gm 0.11 Raspberry flavoring gm 0.02 Ethanol (pure) gm 2.00 Distilled water, qs. ad cc 100.00

10 cc. contain 50 nigm. 1-p-chlorophenyl-2,3-dimethyl- 4-dimethyiamino-butanol-(2) About 50 cc. of the distilled water are heated to (1., and the p-hydroXy-benzoic esters, the sugar, the saccharin-sodium, the tartaric acid, the sec, sodium phosphate and the 1-p-chlorophenyl-2,3-dimethyl-4-dirnethyl amino-butanol-(Z) are dissolved therein. A solution of the eucalyptus-menthol flavoring and raspberry flavoring in the remaining amount of Water is then stirred into the ethanol. The two solutions are combined and the resulting solution is then filtered until clear.

EXAMPLE XXIII A mixture of the 1-p-chlorophenyl-2,3-dirnethyl-4-dimethylamino-butanol-(Z) and the calcium phosphate is moistened with 80% ethanol, and the moist mass is granulated by passing it through a screen having a mesh width of 1 mm., and is then dried at 45 C. to obtain granulate A. A mixture of the lactose and the potato starch is moistened with an aqueous 15% solution of the soluble starch, and the moist mass is granulated by passing it through a screen having a mesh width of 1 mm., and is then dried at 45 C. to obtain granulate B. The two granulates are then admixed with the remaining additives and pressed into tablets having a diameter of about 9 mm.

EXAMPLE XXIV Coated pills:

The tablets obtained in accordance with Example XXIII are coated in known manner with a thin shell consisting substantially of sugar and talcum. The coated pills are polished by means of beeswax.

Total weight of a pill: 350 mgm.

EXAMPLE )QiV Suppositories:

1 suppository contains Mgm. 1 p chlorophenyl-2,3-dimethyl-4-dimethylamino butanol-(2) 50.0 Suppository base (cocoa butter) 1670.0

Total weight 1720.0

The active ingredient is passed through a screen having a mesh width of 0.15 mm. and is then added to the molten cocoa butter at 37 C. The resulting mixture is cooled with stirring to 32 C. and poured into precooled suppository molds.

EXAMPLE XXVI Infant suppositories:

1 suppository contains- Mgm.

1 p chlorophenyl-2,3-dimethyl-4-dimethylamino butanol-(Z) 25.0 Suppository base (cocoa butter) 975.0

Total weight 1000.0

The compounding procedure is the same as in Example XXV.

EXAMPLE XXVII Ampoules:

1 ampoule contains- 1 p chlorophenyl-2,3-dimethyl-4-dimethylamino butanol-(2) mgm 20.0 Sodium chloride mgm 5.0 Double-distilled water, q.s. ad cc 2.0

The 1 p-chlorophenyl-2,3-dimethyl-4-dimethylaminobutanol-(Z) and the sodium chloride are dissolved in a little of the double-distilled water, and the solution is diluted with the remaining water to the desired volume. The resulting solution is filtered until free of suspended particles, filled into white 2 cc. ampoules, and the ampoules are sterilized for thirty minutes at 100 C.

It is obvious that the l-p-chlorophenyl-Z,3-dimethyl-4- dimethy-lamino-butanol-(2) is used merely as an illuswherein: 5 i T R is selected from the group consisting of hydrogen,

chlorine, bromine and methyl,

R is lower alkyl with 1 to 2 carbon atoms,

R is selected from the group consisting of lower alkyl, lower alkenyl, phenyl and benzyl, and

.11 and R are selected from the group consisting of methyl, ethyl and, together with each other and the nitrogen atom, pyrrolidyl and piperidy-l heterocycles,

their racemates, optically active antipodes and non-toxic, pharmacologically acceptable acid addition salts.

2. 1 p chlorophenyl-2,3-dimethyl-4-dimethylaminobutanol-(2).

3. 1 phenyl 2,3-dimethyl-4-dimethylamino-butanol- (2).

4. 1 phenyl 2 ethyl-3-methyl-4-dimethylaminobutanol (2).

5. 1 o chlorophenyl-2,3-dimethyl-4-dimethylaminobutano1-( 2) 7. 1 m tolyl-2,3-dimethyl-4-dimethylamino-butanol- 8. 1 p tolyl-2,3-dimethyl-4-dimethylamino-butanol- (2).

9. 1 phenyl 2 methyl-3-benzyl-4-dimethylaminobutanol-(Z).

10. 1 p brornophenyl-2,3-dimethyl-4-dimethylamind butanol-(Z).

References Cited in the file of this patent UNITED STATES PATENTS 2,665,278 Schultz Jan. 5, 1954 2,717,895 Sprague et a1 Sept. 13, 1955 2,765,307 Schmidle Oct. 2, 1956 2,771,469 Schultz Nov. 20, 1956 FOREIGN PATENTS 529,490 Canada Aug. 21, 1956 532,969 Canada Nov. 13, 1956 6. 1 phenyl 2,3 dimethyl-4-(piperidyl-1)-butanol- V 

1. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF BASIC-SUBSTITUTED CARBINOLS OF THE FORMULA 